Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been prepared with great success. There has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides in the last decade.
The preparation and use of synthetic peptide combinatorial libraries has been described for example by Dooley in U.S. Pat. No. 5,367,053; Huebner in U.S. Pat. No. 5,182,366; Appel et al in PCT WO 92/09300; Geysen in published European Patent Application 0 138 855 and Pimmg in U.S. Pat. No. 5,143,854. Such peptide SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library that identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds that can maintain high affinity and specificity toward biological receptors, while exhibiting improved pharmacological properties relative to peptides. Combinatorial approaches have recently been extended to “organic” or non-peptide libraries.
Combinatorial organic synthesis on solid supports has thus emerged as an important tool in lead structure identification and optimization in drug discovery. [For reviews, see: (a) Hall et al., J. Comb. Chem. 2001, 3, 125; (b) Wendeborn et al., S. Acc. Chem. Res. 2000, 33, 215; (c) Houghten et al., J. M. J. Med. Chem. 1999, 42, 3743; (d) Brown, J. Chem. Soc., Perkin Trans. 1 1998, 3293; (e) Hermkenset al., Tetrahedron 1997, 53, 5643; (f) Balkenhohl et al., Angew. Chem., int. Ed. Engl. 1996, 35, 2288; (g) Thompson et al., Chem. Rev. 1996, 96, 555; and Thompson et al., J. A. Chem. Rev. 1996, 96, 555.] The focus of this field of research is now on the synthesis of small organic molecules on the solid-phase. [(a) Nefzi et al., Chem. Rev. 1997, 97, 449; and b) Fruchtel et al., Angew. Chem., int. Ed. Engl. 1996, 35, 17.] Heterocyclic compounds have received special attention in combinatorial synthesis due to their high degree of structural diversity and biologically interesting properties. [Robert, J. Comb. Chem. 2000, 2, 195.]
Triazinetriones are an important class of molecules with pharmaceutical [(a) Hempel et al., J. Med. Chem. 1989, 32, 648; (b) Atassi et al., Eur. J. Cancer 1980, 16, 1561. (c) Wu et al., Mol. Pharmacol. 1983, 23, 182.] and agricultural [(a) Hagemann, Ger. Offen. 1 927 (1970); C. A. 1971, 74, 42392; and (b) Lindner et al., European Patent Application EP 364 765 (1990); C. A. 1990, 113, 152470.] utility including effective herbicides [Hagemann, Ger. Offen. 1 927 (1970); C. A. 1971, 74, 42392], drugs against coccidosis [Lindner et al., European Patent Application EP 364 765 (1990)] and animal growth stimulators. [Haberkorn, A.; Scheer, M.; Stoltefuss, J. Ger. Offen. 2 718 799(1978); C. A. 1979, 90, 104020.]
An example of such biologically interesting triazinetrione derivatives is Toltrazuril (shown below). This compound has coccidiocidal action and damages all intracellular developmental stages of the schizogony cycles and of the gametogony phase and is an approved anticoccidial therapeutic. [Haberkorn et al., VMR, Vet. Med. Rev. 1987, 1, 22; C. A. 1988, 108, 15842.]
Symmetrically trisustituted triazinetriones have previously been synthesized in solution from isocyanates by a broad range of catalysts such as Lewis acid [(a) Kogon, J. Am. Chem. Soc. 1956, 78, 4911; and (b) Tang et al., J. Org. Chem. 1994, 59, 4931], anions [(a) Kogon, J. Org. Chem. 1959, 24, 83; and (b) Nambu et al., J. Org. Chem. 1993, 58, 1932], and organometallics [(a) Herbstman, J. Org. Chem. 1965, 30, 1259; and (b) Flamini, Tetrahedron Lett. 1987, 28, 2169]. However, most of these conventional methods require severe conditions and are not suitable for solid-phase synthesis. Other approaches to the synthesis of substituted triazinetriones are found in the patent literature [(a) Hagemann, Ger. Offen. 1 927 921(1970); C. A. 1971, 74, 42392; (b) Gallenkamp et al., Ger. Offen. 3 516 632(1986); C. A. 1987, 106, 67355; and (c) Lantzsch, Ger. Offen. 3 516 631(1986); C. A. 1987, 106, 67356] in which, such compounds are prepared by the cyclocondenation of isocyanate with ureas and diethyl carbonate or ureas are cyclocondensed with chlorocarbonyl isocyanate.
It is therefore clear that prior art syntheses of triazinetriones are in need of improvement. The disclosure that follows is directed to new triazinetriones. That disclosure further extends the combinatorial solid phase synthesis of individual small heterocyclic molecules to include triazinetriones and libraries thereof using amino acids as starting materials [(a) Ostresh et al., J. Org. Chem. 1998, 63, 8622; (b) Yu et al., Tetrahedron Lett. 2001, 42, 623; (c) Yu et al., Organic Letters. 2001, 3, 2797; and (d) Acharya et al., J. Comb. Chem. 2001, 3, 189] through the use of techniques that help overcome the several disadvantages in the prior syntheses of such compounds.